Renal epithelial cells may be useful in treating renal disorders. This includes applications inbio-artificial kidney devices to replace or compensate for lost organ functions. Thus, a sufficient supply of renal epithelial cells is required. Of particular interest are renal proximal tubular cells (PTC), which perform various renal functions.
Renal proximal tubular cells function in drug transport and metabolism, and thus are also of particular interest for in vitro nephrotoxicology. This cell type is a major target of drug-induced toxicity in the kidney. Many widely used marketed drugs, including anti-cancer drugs, antibiotics, immunospressants and radiocontrast agents, tend to be nephrotoxic and thus may injure proximal tubular cells in the kidney. Drug-induced nephrotoxicity is a major cause for acute kidney injury (AKI).
Nonetheless, the prediction of nephrotoxicity during drug development remains difficult. Typically, compound nephrotoxicity is only detected during the later stages of drug development. Pre-clinical animal models have limited predictive success; the development of in vitro models for assaying nephrotoxicity that demonstrate strong predictivity has been challenging. Most existing in vitro assays systems have been based on established cell lines. Primary renal proximal tubular cells are only available in limited amounts and can be affected by inter-donor variability and functional changes during in vitro cultivation and passaging.
Previous technology described a method for differentiation of human embryonic stem cells (hESCs) into cells expressing aquaporin (AQP)-1. In the kidney, AQP-1 is specifically expressed in proximal tubular cells. About 30% of the hESC-derived cells expressed AQP-1, and further analyses showed that hESC-derived cells were similar to human primary renal proximal tubular cells (HPTC) cultivated in vitro with respect to gene and protein expression patterns and morphological and functional features. hESC-based technologies are affected by ethical and related legal issues, which may compromise commercialization. Also, the relatively low rate (30%) of hESC-derived HPTC-like cells is a problem, and purification procedures would be required in order for such HPTC-like cells to be useful in any practical applications. Further, hESC-derived cells express some major drug transporters like the organic anion transporter (OAT)3 at very low levels, which may compromise application of such cells in in vitro nephrotoxiclogy.